DIBENZA-{8 b,f{9 -S-TRIAZOLO-{8 4,3-d{9 {8 1,4{9 OXAZEPIN-3-(2H)-ONES

ABSTRACT

Compounds of the formula III:   wherein R1 is selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms, inclusive and   IN WHICH R7 and R8 are hydrogen and alkyl, as defined above and n is 2 or 3, or together   IS PYRROLIDINO, PIPERIDINO OR N-methylpiperazino; wherein R3 and R4 are hydrogen, fluoro, chloro, bromo, nitro, alkyl defined as above, trifluoromethyl, or alkoxy, of 1 to 3 carbon atoms, inclusive, are prepared by reacting a thio compound of formula I:   wherein R3 and R4 are defined as above, in sequence; 1. WITH AN ALKYLCARBAZATE; AND THE RESULTING INTERMEDIATE PRODUCT II 2. with an alkylating agent of the formula R1&#39;&#39;X in which R1&#39;&#39; is alkyl,   AS DEFINED ABOVE AND X is chlorine, bromine, or iodine, to obtain a compound III as defined above. Compounds of formula III and the pharmacologically acceptable acid addition salts thereof have anti-depressant activity and tranquilizing activity and can be used in mammals.

United States Patent, 1191 Szmuszkovicz [75] Inventor: JacobSzmuszkovicz, Kalamazoo,

Mich.

[73] Assignee: The Upjohn Company, Kalamazoo,

' Mich. i

22 Filed: Aug. 7, 1973 21 Appl.No.:386,278

Related US. Application Data [63] Continuation-impart of Ser. No.307,113, Nov. 16,

1972, abandoned, which is a continuation-in-part of Ser. No. 220,405,Jan. 24, 1972, abandoned.

[56] References Cited UNITED STATES PATENTS 2/1972 Hester 260/308CPrimary Examiner-Alton D. Rollins 57 ABSTRACT Compounds of the formula111:

wherein R is selected from the group consisting of hydrogen, alkyl of lto 3 carbon atoms, inclusive and VanDer Burg 260/268 PC 1111 3,853,9041451 Dec. 10,1974

in which R, and R are hydrogen and alkyl, as defined above and n is 2 or3, or together is pyrrolidino, piperidino or N-methylpiperazino; whereinR and are hydrogen, fluoro, chloro, bromo, nitro, alkyl defined asabove, trifluoromethyl,

or alkoxy, of l to 3 carbon atoms, inclusive, are prepared by reacting athio compound of formula 1:

R I R4 7 wherein R and R are defined as above, in sequence;

1. with an alkylcarbazate; and the resulting intermediate product 11' 2.with an alkylating agent of the formula R 'X in which R, is alkyl, 1

as defined above and X is chlorine, bromine, or iodine, to obtain acompound III as defined above. Compounds of formula III and thepharmacologically thereof I have anti-depressant activity andtranquilizing activity and acceptable acid addition salts can be used inmammals.

13 Claims, N0 Drawings CROSS REFERENCE TO RELATED 4 APPLICATIONS This isa continuation-in-part of application Ser. No. 307,113 filed Nov. 16,1972, and now abandoned which is a continuation-in-partof applicationSer. No.

220,405, filed Jan. 24, 1972 and now abandoned.

BACKGROUND 0; THE INVENTION Field of the Invention This invention isdirected to new organic compounds and is particularly concerned withnovel compounds II and Ill and a process for the production thereof.

The novel compounds and the process of production therefor can beillustr'atively represented as follows:

R: F i

l h in wherein R, is alky of l to 3 carbon atoms, inclusive or in whichR and R are hydrogen above, and n is 2 or 3 or together 1" wherein R isalkyl of Ho 3 carbon atoms, inclusive,

(CH2)n N above, and wherein &,' and chloro, or bromo.

The most desirable products of this invention have in which n is 2 hr 3,and R," and R 'are alkyl of 1 to 3 carbon atoms, inclusive; and whereinR and R or alkyl, defined wherein n, R, andRg or is pyrrolidino,N-methylpiperazino, or piperidino;

wherein R and R, are hydrogen, fluoro, chloro, bromo, alkyl The moredesirable products the formula IIIA I which R is alkyl of l to 3 carbonatoms, inclusive, or

are defined as above.

' DESCRIPTION OF THE PREFERRED EMBODIMENT Lower alkyl groups of l to 3carbonatoms, inclusive,

in which n is 2 or 3 and R, and R are alkyl defined as I R, arehydrogen,.fluoro,

I 3 are eitemplified by methyl, ethyl, propyl, and isopropyl.

- The carbon chain moiety of alkoxy, which is of l to 3 carbon atoms,inclusive, can be defined as loweralkyl of l to 3 carbon atoms,inclusive,.as above.

The novel compounds of formula III and pharmacologically acceptable acidaddition salts thereof have tranquilizing and antidepressant activityand are thus useful for the treatment of depression and anxiety inmammals or birds.

For example the tranquilizing and sedative activity of 2-[ 2-(dimethylamino)ethyl ]diben2o[b,f1-striazolo[4,3-d]-[l,4]oxazepine-3(2H)-one (test Compound A) was determined as foliolwsz'Chimney test:

(Med. Exp. 4, 'l l- (.1961 )1: The'effective intraperitoneal dossage for50% of the mice (B1) is 36 mg./kg. The test determines the ability ofmicet'o back up and out of a vertical glass eylinderwithin 30-seconds Atthe effective dosage, 50% of the mice failed doing it. Dish test:

Micein Petridishes (.10 an. diameter, an. high,

. partially embedded in wood shavings), climb out in a tablish=theanti-depressant action if present. A number g i of such tests aredescribed below.

Hypothermic tests with oxotremorine: (pyrrolidinyl )-2-butynyl]2-pyrrolidinone Oxotremorine (as well as apormorphine and tetrabenazine)produces hypothermic responses in mice. This response is blockedbyanticholinergics and antidepressants suchas atropine and imipramine.

Oxotremorine produces a very pronounced hypothermia which tration.

decreased about 13 F. (.when the mouse is kept at roomtemperature)."l'his temperature decrease is antagonized byanti-depressants e.g. desipramine, imipramine, doxepine, and others ascan be seen from Table TABLE 1 Efiect of Various Compoundson'Oxotremorine Induced Hypothermia in Mice Dose Body Temperature"F-Change mg.lkg., Absorption From Vehicle Control Afler Com- 1. P. Time(min) Minutes pound oxotremorine (Conv trol) 0.6 S.8 1.6 l 3.2 8.0Desipramine 3.5 3.5. 4.1 3.6 lmipraf i nine 25 30 -0 .4' 3.3. 5.6 6.4rmole 25 30 63 l 1.8 'l2.8 l 1.9 D oxcv pine 4 25 30 2.3 7.| ll.0 l2.3A'mitriptyline 25 30 +0.7 2.4 5.4 6.8 Ampheta- I mine 5 30 l.5 4.3 4.42.2 Atropine 3 30 +0.6 0.6 0.2

. very short time, when not treated. Mice remaining in the dish formorethan 3 minutes indicates tranquilization. ED equals the dose of thetest compound at which 50% of the mice remain in the dish. The ED 1(intraperitoneal administration) for this test compound A is 3.6 mgJkg.

Pedestal test: i I V The untreated mouse leaves the'pedestal in lessthan a minute to climb back to the floor of the standard mouse box.Tranquilized mice will stay on the pedestal Y Y lants such as theamphetamines which produce over stimulation in the normal individual.

Many different methods have been and are used to evaluate antidepressantactivity. In general these meth-' g ods involve antagonism to adepressant such as resersured rectally with an electronicthermometer,-before and 30 minutes afterdrug administration. After thedrug administration the mice were kept at 19 C. .in cages. A rise of 4F. of the body temperature of the treated animal against the controlanimal shows activity. The test compound showed this activity at adosage of 25 mg./kg.

LD of yohimbine hydrochloride in mice is rag/kg. i.p. Administration of30 'mgJkg. of yohimbine hydrochloride was non-lethal. If anantidepressant is admi'nis tered prior to the yohimbine hydrochloride(30 mg.)

the lethality of creased.

Ten male CF mice. 18-22 g., were injected with yoithe yohimbinehydrochloride is inhimbine hydrochloridein' saline solution. Aftertworeaches a peak 6- minutes after adminis- At 0.6 mgjkgrthe bodytemperature of a mouse is The test-compound tested as follows. Four IPotentiation ofyohimbineaggregation toxicity: the

administration of yohimbine hydrochloride [YCl] (30v mg. No mice or onlyone mouse is killed from 30 mg. of [YCI]. If [YCl] is administered inthe presence of an anti-depressant an increase in the toxicity of [YCl]is found. The ED value of the test compound-A causing 50% of the mice todie is 8.8 mg./kg.

Potentiation of apomorphine gnawing: a group of 4 mice (male, CF 18-22g.) are administered the test compound A intraperitoneally one hourprior to the subcutaneous injection of apomorphine hydrochloride mg./kg.The mice are then placed in a plastic box (6 X 11 X 5") lined at thebottom with a cellophanebacked, absorbent paper. The degree of damage tothe paper at the end of 30 min. is scored from zero to 4. The scores 3and 4 indicate that the compound is a potentiator of apomorphine in thistest. Test compound A was positive in this test at 35 mg./kg. in mice.

2-[3-(dimethylamino)propyl]dibenzo[b,f]-striazo1o-[4,3-d][l,4]-oxazepin- 3(2H)-onehydrochloride is active in the yohimbine test at35 mg./kg., and apomorphine test at 30 mg./kg., in the chimney test at18 mg./kg. in the dish test at 2.8 mg./kg., in the pedestal test at 10mg., and in the nicotine test at 2.5 mg./kg.

The above results show that compounds of formula III and thepharmacologically acceptable acid addition salts thereof can be used astranquilizer and antidepressants in mammals to achieve normalcy in thedepressed individual, and to overcome anxiety.

The pharmaceutical forms of compounds of formula with trichloroaceticacid are useful as herbicides against Johnson grass,'Bermuda grass,yellow and red foxtail, and quack grass.

The starting materials of this invention aredihydrodibenzoxazepinethiones l which are either known or can besynthesized, for simplicity by treating the corresponding oxazepinecompounds with phosphorus Ill, and the pharmacologically acceptable acidaddition salts thereof can be used as tranquilizer and antidepressantsin mammals to achieve normalcy in the depressed 1 individual, and toovercome anxiety.

The pharmaceutical forms of compounds of formula III, and salts thereofcontemplated by this invention include pharmaceutical compositionssuited for oral, pa-.

renteral, and rectal use, e.g., tablets, powder packets, cachets,dragees, capsules, solutions, suspensions, sterile injectable forms,suppositories, bougies, and the like. Suitable diluents or carriers suchas carbohydrates, lactose, proteins, lipids, calcium phosphate,cornstarch, stearic acid, methylcellulose and the like may be used ascarriers or for coating purposes. Water or oils such as coconut oil,sesame oil, safflower oil, cottonseed oil, and peanut oil, may be usedfor preparing solutions or suspensions of the active drug. Sweetening,coloring, and flavoring agents may be added.

For mammals .food premixes with starch, oatmeal,

I dried fishmeat, fishmeal, flour, and-the like can be prepared.

As antidepressants and tranquilizers the compounds of formulae II and111 (including 111A and IIIB) their pharmacologically acceptable acidaddition salts can be used in dosages of 0.5-25 mg./kg., with 1-15 mg.preferred, in oral or injectable preparations as described above toalleviate anxieties and depressions occurring in stressful situations.Such situations are those for example, where animals are changingownerships or are temporarily put into kennels while their owners areabsent from home. In larger animals, 10 kg. and more, the lower dosageranges are preferred.

Acid addition salts of the compounds of formula 111 can be made, such asthe fluosilicic acid addition salts which can be applied as mothproofingagents, and salts pentasulfide as further illustrated by thePreparations.

Useful 10,1 l-dihydro-l 1-oxo-dibenzo[b,f]-1,4- oxazepines and theirsynthesis are in particular disclosed by Schmutz et al., I-Ielv. Chim.Acta. 48, 336 (1965).

In carrying out the process of this invention, a selected thione I, isheated with an alkyl carbazate of the formula:

H NNI-I-COOAlk in which the alkyl group is of l to 3 carbon atoms,inclusive. Usually ethyl carbazate is preferred, but higher alkylcarbazates are. operative. In

the preferred embodiment of this invention, the selected thione I isheated with ethyl carbazate in large excess for /2 hour to 3 hours at190 to 250 C. in an oil bath. The alkyl carbazate serves simultaneouslyas.

reagent and solvent. The product usually precipitates upon cooling ofthe reaction mixture and is recovered by filtration and purified byconventional means, e.g., extractions of impurities, chromatography ormost commonly by recrystallization. The triazolone compound II is thus,obtained.

' is defined as above. Both reactions, formation of salt and thereaction of this salt with R X; are usually performed at elevatedtemperatures between 50 to C. The conversion of II to its alkali salt isusually performed during 15-75 minutes. The reaction of the saltv withthe chloride is carried out during a longer period of time by keepingthe reaction mixture at the elevated temperature for l to 36 hours. Theproduct 111, thus obtained, is isolated and purified by conventionalmeans e.g. extraction, chromatography, crystallization and the like.

The following preparations and examples are illustrative of theprocesses and products of the present invention, but are not tobeconstrued as limiting. Preparation 1 dibenzo[b,f] [1 ,4]oxazepine-l 1(101-1)- thione I A mixture of 1 l( 1OH)-one (10 g.) phosphoruspentasulfide (23.3 g.; 0.105 mole) and 830 ml. of pyridine is heated atreflux temperature for 5 hours and the pyridine is evaporated in vacuo.The residue is stirred with chloroform, and 400 ml. of saturated aqueoussodium bicarbonate solution is added. The resulting suspension isfiltered and the solid is discarded. The filtrate is separated intolayers, and the organic layer is washed successively with aqueous sodiumbicarbonate and with saturated salt solution, dried over anhydrousmagnesium sulfate and evaporated. The residue was crystallized frommethylene chloride-methanol to give 2-fluoro-dibenzo- Other startingmaterials of formula I are produced as shown in the precedingPreparations. Such starting materials include:

thione; 4,-7-dibromodibenzo[b,f}[ l ,4]oxazepine-l l( lH)- thione;

2,8-methoxy-l l H-dibenzo[b,f][ l ,4]oxazepine- 1 l( H )-thione;

1 l( l0H)-thione; 4-ethyl-dibenzo[b,f][ l,4.}oxazepine-l l 10H) thione;

,1 -methyl- 1 -dibenzo[b,f] 1,4]oxazepine-l l 10H)- thione; l-bromo-2,5, l O-dihydro-l ll-ldibenzo[b,f] l ,4]oxazepine-l l-(10H)-thione; 2,8-difluoro-l lH-dibenzo{ b;f][ l,'4loxazepinel l(l0H)-thione; 1-methyl-9-chloro-dibenzo[ b,f][ l ,4]oxazepinl l(10H)-thione;

l l( l0H)-thione', 4-methoxy-6-nitrodibenzo[b,f][ l ,4]oxazepinl 1(10H)-thione; and the like.

EXAMPLE 1 thione (2.59 g., 0.0l mole) and ethyl carbazate (10.4

Anal. calcd. for C HN O C. 66.93; H. 3.61; N. 16.73.

Found: c. 66.70; H, 3.53; N, 16.85.

EXAMPLE 2 2-[ 2-( Dimethylamino )ethyl ]dibenzo[b,f]-striazolo[4,3-d][l,4]oxazepin-3(2H)-one Sodium hydride (0.218 g., 5.17 mmoles of 57%suspension in mineral oil) is added to a solution of dibenz-j g., 5.17mmoles) in 50 ml. of dimethylformamide and the mixture is heated for 30minutes at 95". C. A solution of Z-dimethylaminoethyl chloride (0.555g., 5.17 mmoles) in 0.555 g. of xylene is added and the mixture heatedat 95C. for l7 hours and evaporated. Water and'methylene chloride wereadded. The organic layer was extractedwith 10% aqueous hydrochloric acid(3 X ml.), the acidic extract was washed with ether (discard ether),cooled, basified with aqueous sodium hydroxide and extracted withmethylene chloride. The organic solution was washed with saturated saltsolution, dried and evaporated. The crude product thusobtained wascrystallized from ether and petroleum ether (b. p. 3060) to give0.65 g.of 2-[2-' (dimethylamino )-ethyl ]dibenzo[ b,f]-s-triazolo[ 4,3-d][l,,4]oxazepin-3(2H)-0ne of melting point l09lll C. Afterrecrystallization from ether the melting point was lO3-l04 C.

EXAMPLE 3 2[ 3-(dimethylamino)propyl }dibenzo[ bf] -striazolo[4,3-d][l,4]oxazepin.-3( 2H)-one and its hydrochloride ln the manner given inExample 2, dibenzo[b,f]-striazolo[ 4,3-a][ 1,4]ozazepine-l 1( [0H )-onewas treated with sodium hydride and theresulting product was treatedwith 3-(dimethylamino)propyl chloride to give --l0.l g. of2-[3-(dimethylamino)propyl1dibenzo[b,f]-s-triazolo[4,3-d][ l,4]oxazepin-3( 2H)-one as an oil. The hydrochloride was formed in etherand crystallized from methanol-ether to give 8.8 g. of 2-[3-(dimethylamino)propyl]dibenzo[b,f]-s-triazolo-[4,3-d][l,4]oxazepin-3(2H)-one hydrochloride of melting point 1s3-1s4 c.

Anal. calcd. for C H N O .HCl.l.5H O: A

C, 5714'; H, 5.93; C], 8.88; N, 14.03, Found: C, 57.37; H, 5.41; Cl,9.04',.N, l4.54.

EXAMPLE 4 EXAMPLE 5 In the manner given in Example 2, dibenzo[b,f]-s-'triazolo[4,3-d] l ,4]oxazepin-l l( lOH)-one was treated with sodiumhydride and l-2-chloroethyl)piperidine to give after extraction withhydrochloric acid 2-[2-(1- piperidinyl )ethyl -dibenzo[ b,f]-s-triazolo[ 4,3-

d][ l ,4]oxa.zepin-2H-one dihydrochloride.

' EXAMPLE 6 2- 2-( phthalirnido )ethyl ]dibenzo b,f]-s-triazolo- 4,3-

in the manner given in Example 2,dibenzo[b,f]-striazolo[4,3-d][l,4]oxazepin3(2l-l)-one is first reactedwith sodium hydride, and the resulting product withN-(2-bromoethyl)phthalimide to give 2-[2-(phthalimido)ethyl]dibenzo[b,f]-s-triazolo[4,3-

EXAMPLE 7 I mmole), hydrazine hydrate (0.0179 mole) and 25 ml.

of ethanol was stirred at room temperature for 24 trate evaporated. Theresidue is dissolved in methylene chloride and water. The organic layerwas washed with water, dried over anhydrous magnesium sulfate andevaporated to give 2-[2-(amino)ethyl]dibenzo[b,f]-striazolo[4,3-d][l,4]oxazepin-3(2H)-one.

' EXAMPLE 82-[2-(benzylmethylamino)ethyl]dibenzo[b,f]-striazolo[4,3-d]xazepin-3(2l-l)-one1n the manner given in Example2,.dibenzo[b,f]-striazolo[4,3-d][l,4]oxazepin-3(2H)-one is first reactedwith sodium hydride, and the resulting product withN-benzyl-N-methyl-2chloroethylamine to give 2-[2-(benzylmethylamino)-ethyl]dibenzo[b,f]-striaz0lo[4,3-d][ 1,4]oxazepin-3( 2l- 1)-one.

' EX MPLE 9 2- 2-( methylamino )ethyl dibenzo b,f] -s-triazolo- 4,3- d][l ,4]oxazepin-3(2H)-one mixture of 2-[2- (benzylmethylamino )ethyl]dibenzo['b,f]-striazolo[4,3-d][ l ,4]oxazepin-3(2H)-one (0.03 67 mole),palladium 1.1 g. of 10% palladium on carbon, 74 ml. of 1N etherealhydrogen chloride (0.0735 mole) and 240 ml. of methanol was hydrogenatedat 50 psi until absorption of hydrogen was complete. The mixture wasfiltere'd'and the filtrate evaporated to give 2- EXAMPLE l0 EXAMPLE 1 l7-Chloro-dibenzo[b,f]-s-triazolo[4,3-d][ 1.4 oxazepin-3(2H)-one Amixture of 7-chloro-dibenzo[b,f][1,4]0xazepine- 10 In the manner givenin Example 2, 7- chlorodibenzolb,f]-s-triazolo[4,3-d][ l,4]oxazepin'- 3(2H)-one, sodium hydride and 2- (dimethylamino)ethyl chloride gave7-chloro-2-[2- (dimethylamino)ethyl]dibenzo[b,f]-s-triazolo[4,3-d]

[l,4]oxaze'pin-3(2H)-one of melting point l36138,

. Anal.calcd. rorc.,1-1,,C1N.o,Hc1;

raised upon recrystallization from ether to l42-l43 C.. I

Anal. calcd. for C H CIMC C, 60.59; H. 4.80; C], 9.94; N, 15.70.

Found: C. 60.48; H. 4.88; Cl 5.92.

EXAMPLE 13 triazolo[4,3-d][ l,4]oxazepin-3(-2H)-one and itshydrochloride1n the manner given in Example 2, 7-chloro- 3(2H)-one was treated withsodium hydride and then I with 3-(dimethylamino)propyl chloride to give6.9 gm. of 7-chloro-2-[3-(dimethylamino)-propyl]dibenio[b,f]-s-triazolo[4,3 d][1,4]oxazepin- 3(2H)-one as'an oil.The hydrochloride was prepared in ether and hada melting point of 228",229 C.

, C, 56.03; H, 4.95; Cl. 17.41; Found: C. 56.34; H, 4.93; CI. 17.54

: EXAMPLE 14 carbazate are reacted together at 200215 C. to give 1l(l0H)-thione (15.1 g; 0.058 mole) and ethyl carbazate (60.3 g.; 0.58mole) was heated in an oil bath at 205 -215 C. for one hour using a takeoff condenser. The mixture was cooled to 40 C.-, shaken with 200 ml. ofwater for for 3 hours until a fine suspension resulted and filtered. Thesolid was washed with water and then ether to give 14.7 g. of7-chloro-dibenzo[b,f]-striazolo[4,3-d]-[l,4]oxazepin-3(2H)-one ofmelting point 3l3-314 C. This was unchanged on crystallization frommethanol-chloroform.

Anal. calcd. for C H CIMO C. 58.86; H. 2.82; Cl. 12.41; N, 14.71. Found:C. 58.85; H. 2.90; C1. 12.59; N, 14.69.

EXAMPLE l2 3(2H)-one.

EXAMPLE l5 In the manner given in Example 2, 7efluoro- 3(2I-1)-one isfirst reacted with sodium hydride, and the resulting product with2-(dimethy lamino)ethyl chloride to give 7-fluoro-2-[2- zate are reactedtogether and 200-2l5 C. to give 10-propyldibenzo[b,f]-s-triazolo[4,3-d][ l ,4]oxazepin- In the manner givenin Example I, 4-propyl-dibenzo- [b,f][ 1,4]0xazepin-l 1( l0l-l)-thioneand ethyl carba- EXA PLE 17 J 2-Ethyl-dibenzo[b,f]-s-triazo1o[4,3-d] l,4]-oxazepin- In the manner given in Example 2, dibenzo-[ bfl-striazolo[4,'3-d][ l ,4]okazepin-3(2H)'-on'e was first treated withsodium hydride and then with ethyl-bro-' mide to give2-ethyldibenzolb.f]-s-triazolo[4,3-

. EXAMPLEIS 7,1 l-Dichlorodibenzo[b,f] s-triazolo[4,3-d]- l ,4 a PH)-one In the; manner, given in Example l, '3,7'-

-dichlorobenzo[b,f][ 1 ,4loxazepin- 1 1 1011 )-thione and ethylcarbaiate are reacted together at 2002 1 5 C. to give r 7,ll-dichlorodibenzo[b,f]-s-triaz0lo[ 4,13% d][ l',4]oxazepin-3(2H)-one. II

- EXAMPLE 19 (dimethylaminomropylldibenzo[b,f]-s triaizol0[ 4,3- d]{ l,4]oxazepin- 3 (-2H)-one 3( 2H )-one is first reacted with sodiumhydride and the resulting product with" 3:(dimethylamino )propylchloride 1 to I give 7,ll-diehloro-2-l3-(dimethylamino)propyl1dibenzo[b,f}-s-triazolo[4,3- d]-[ l,4]oxazepin-3(2H )-one.

3(2H )-one is first treated with sodium hydride and then r with t ethylbromide to I give 6,1 l-difluoro2- propyldibenzo[ b,f]-s-triaZolo[4,3-d1,4]oxazepin- 3 2H l-one.

EXAMPLE 22 6,1 l-difluoro-2-[2-(diethylamino)ethyl]dibenzo-[b,f] 1

s-triaz olo 4,3-d l- ,4 }oxazepin-3( 2H )-orie In the manner given inExample 2, 6,11-

' difluorodibenzofbfl-s-triazolo[4,341] l-,4]oxazepin- 3(2H)-one isfirst treated with sodium hydride and then with 2-(diethylamino)-ethylbromide to give 2-[2- carbazate are reacted together at 2009-2 I S C. to7. -dibromodibenzo[b,f] -s-triazolo[4,3- d][ l,4]oxazepin-3(2H )-one.

" 3(2H)-one was first treated with sodium-hydride and then with3-piperidin0propyl bromide to give 7-nitro-2- In the manner given inExample 1, 7-nitro-dibenz0- EXAMPLE24 [2-(dipropylamino)ethyl1-7,lO.-dibromodibenrcol bf]- EXAMPLEEZS In the .manner given in Example 1,2,8-

and ethyl carbazate are reacted together at 200215 d][1 ,4]oxazepin'3(2H)-orie was first treated with sodium hydride and then with methylbromide to give 2- methyl-, l 2 dimjethoxy'-dibenzo b,f] -s-triazolo[4,3- d][ l,4]ox azepin-3 2H)-one.

' zate are reacted together at 200-2l5 C. to give 7- EXAMP LB 2'3Z-(Pyrrolidinoethyl )-7nitro-dibenz0[b,f] s- I In the manner given inExample 2, 7-nitr0- I dibenzolbfl-s-triazolol4,3-d l ,4]oxazepin-'3(2H)-one was first treated with sodium hydride and, give 2- then withpyrrolidinoethyl bromide to (pyrrolidinoethyl)-7-nitro-dibenzo[b,f]

I EXAMPLE 29 I 7-nitro-3-piperidinopropyldibenzo[b,f]-s-triazolo[4,3-

i [n the manner given in- Example 2,7-nitrodibenz0[b,f]-s-triazolo[4,3-d][ l',4]oxazepind][l,4]oxazepin-3(2H)-one. I

' EXAMPLE 30 1n the manner given in Example l,4,7-dibromodibenzo-[b,'f][ l,4]oxazepin-l l( lOH)-thione and ethyl.

g ve

In the manner given in Example 1, 3- nitrodibenzo[b,f]-s-triazolo[1,4]oxazepin-l 1( 10H)- thione and ethyl carbazate are reacted togetherat 200-2l5- C. togivell-nitrodibenzo[b,f]-striazolo[4,3-d]['l,4]oxazepin-3-(2H)-one.

in Exampile ,2, 6,122

EXAMPLE 3l 1 l-Nitro-2-isopropyl-dibenzol b,f]-s-triazolo[ 4,3- d][l,4]oxazepin-3(2H)-one.

in the manner given in Example 2, l l-nitro-dibenzo-[b,f]-s-tria2olo[4,3-d][ l ,4]oxazepin-3(2H)-one is first treated withsodium hydride and then with 2-isopropyl bromide to give 2-isopropyl-ll-nitro-dibenzo[b,f]-striazolo-[4,3-d] [l ,4]oxazepin-3(2H)-one.

EXAMPLE 32 S-Chloro-l 3-methyldibenzo[b,f]-s-triazolo[4,3- d l,4]oxazepin-3(2H)-one In the manner given in Example 1,9-chloro-lmethyldibenzo[b,f][ 1,4]oxazepin-l l(10l-l)-thione and ethylcarbazate are reacted together at 2002l5 C. to give5-chloro-13-methyldibenzo[b,f]-s-triazolo[4,3- d] [1 ,4]oxazepin-3(2H)-one.

EXAMPLE 33 S-Chlorol 3-methyl-2-[( B-piperidinopropyl In the mannergiven in Example 2, '5-chloro-l3- methyldibenzo[b,f]-s-triazolo[4,3-d][l,4]oxazepin- 3(2l-l)-one is first treated with sodium hydride and thenwith 3-(piperidinopropyl)bromide to give 2-[(3- piperidino)propyl]-5-chlorol 3-methyl-dibenzo[b,f]-s-triazolo[4,3-

ln the manner illustrated by the prior examples other compounds offormula Ill can be synthesized. Representative compounds, thus obtained,include:

2-[(Z-methylamino)ethyl]-7-chloro-dibenzo[b,f]-s- 5, lO-dichloro-dibenzo[ b,f]-s-triazolo[ 4,3-

d l ,4]oxazepin-3(2H)-one; 8-isopropyl-dibenzolbf]-s-triazolo[4,3-

d l[ l ,4]oxazepin3(2H)-one;Z-isopropyl-lO-methyl-dibenzo[b,f]-s-triazolo[4,3-

14 2-[ 2 4-methylpiperazino )ethyl ]dibenzo[ b,f] -striazolo-[4,3-dl[l,4Ioxazepin-3( 2H)-one; and the like.

The novel compounds of formula III ("IA and lllB included) can bereacted with selected acids 0. g. hydrochloric,- hydrobromie, sulfuric,phosphoric, tartaric,

citric, lactic, cyclohexanesulfarnic, toluenesulfonic and other acids togive the corresponding pharmaceutically acceptable acid addtion salts.This reaction is carried out under conventional conditions, in solventssuch as ether, dioxane, tetrahydrofuran and the like at roomtemperatures, and the resulting precipitate salts are collected byfiltration. These salts can be used in place of the free base for thesame pharmaceutical purpose described before.

I claim:

1. A compound of the formula:

wherein R is hydrogen, alkyl of l to 3 carbon atoms, inclusive, or

R1 (CH) IN/ 2 n in which n is 2 or 3, and R and R is hydrogen or alkyldefined as above, or together I is pyrrolidino, N-methyl piperazino, orpiperidino; and wherein R and R are hydrogen, fluorine, chlorine,bromine, nitro, alkyl as defined above, trifluoromethyl, or alkoxy of 1to 3 carbon atoms, inclusive and the pharmacologically acceptable acidaddition salts thereof.

2. A compound according to claim 1 of the formula wherein R is alkyl ofl to 3 carbon atoms, inclusive 1s in which n is 2 or 3 and Ri'and arealkyl defined as above; and wherein R and R are hydrogen, fluoro,

chloro, or bromo and the pharmacologically acceptable acid additionsalts thereof.

3. A compound according to claim 1 of the formula Rs" N R4" wherein R isin which n is 2 or 3, R and R are alkyl of l to 3 carbon atoms;inclusive; and wherein R and R are hy drogen or chlorine and thepharmacologically acceptable acid addition salts thereof.

4. A compound according to claim 1, wherein R R v '16 d][ l,4]oxazepin-3(2H)-one.

6. A compound according to claim 3 wherein 'R is3-(dimethylamino)propyl, R and R are hydrogen a and R are hydrogen andthe compound is therefore di- 5. A compound according to claim 3,wherein R is 2-(dimethylamino)ethyl, R and R are hydrogen and thecompound is therefore 2-[2-(dimethylamino)ethyl-dibenzo[b,f]-s-triazolo[4,3-

9. A compound according to claim 3 wherein R 'f is3-(dimethylamino)'propyl, R is hydrogen, R is 7- chloro and the compoundis therefore 7-chloro-2-[3- dimethylamino)propyl-dibenzo[b,f}-striazolo[4,3- d][ 1 ,4]oxazepin-3(2H)-one.

10. The compoundof claim 9 as a hydrochloride.

11. A compound according to claiml wherein R and R are hydrogen R is7-chloro and the compound is therefore d][ l ,4]oxazepin-3(2H)-one.

12. A compound according to claim 3 wherein R is 2-aminoethyl, R and. Rare hydrogen and the compound is therefore 2-[ 2-(aminoethyl)]dibenzo[b,f]-s-triazolo{4,3-d][ l ,4]- oxazepin-3(2H)-one.

13. A compound according to claim 3 wherein R is 2-(methylamino)ethyl, Rand R are hydrogen and the compound is therefore 2 [2- (methylamino)ethyl]dibenzo[b,f]-s-triazolo[4,3-

7-chloro-dibenzo[b,f]-s-triazolo[4,3-

1. A COMPOUND OF THE FORMULA:
 2. A compound according to claim 1 of theformula
 3. A compound according to claim 1 of the formula
 4. A compoundaccording to claim 1, wherein R1, R3, and R4 are hydrogen and thecompound is therefore dibenzo(b,f)-s-triazolo(4,3-d)(1,4)oxazepin-3(2H)-one.
 5. A compound according to claim 3, whereinR1'''''' is 2-(dimethylamino)ethyl, R3'''' and R4'''' are hydrogen andthe compound is therefore2-(2-(dimethylamino)ethyl-dibenzo(b,f)-s-triazolo(4,3-d)(1,4)oxazepin-3(2H)-one.
 6. A compound according to claim 3 whereinR1'''''' is 3-(dimethylamino)propyl, R3'''' and R4'''' are hydrogen andthe compound is therefore2-(3-(dimethylamino)propyl)-dibenzo(b,f)-s-triazolo(4,3-d)(1,4)oxazepin-3(2H)-one.
 7. The compound of claim 6 as hydrochloride.
 8. A compoundaccording to claim 3, wherein R1'''''' is 2-(dimethylamino)ethyl, R3''''is hydrogen R4'''' is 7-chloro, and the compound is therefore7-chloro-2(2-(dimethylamino)ethyl)-dibenzo(b,f)-s-triazolo(4,3-d)(1,4)oxazepin-3(2H)-one.
 9. A compound according to claim 3 whereinR1'''''' is 3-(dimethylamino)propyl, R3'''' is hydrogen, R4'''' is7-chloro and the compound is therefore7-chloro-2-(3-dimethylamino)propyl-dibenzo(b,f)-s-triazolo(4,3-d)(1,4)oxazepin-3(2H)-one.
 10. The compound of claim 9 as ahydrochloride.
 11. A compound according to claim 1 wherein R1 and R3 arehydrogen R4 is 7-chloro and the compound is therefore7-chloro-dibenzo(b,f)-s-triazolo(4,3-d)(1,4)oxazepin-3(2H)-one.
 12. Acompound according to claim 3 wherein R1'''''' is 2-aminoethyl, R3''''and R4'''' are hydrogen and the compound is therefore2-(2-(aminoethyl))dibenzo(b,f)-s-triazolo(4,3-d)(1,4)-oxazepin-3(2H)-one.13. A compound according to claim 3 wherein R1'''''' is2-(methylamino)ethyl, R3'''' and R4. are hydrogen and the compound istherefore2-(2-(methylamino)ethyl)dibenzo(b,f)-s-triazolo(4,3-d)(1,4)oxazepin-3(2H)-one.